This invention relates to the prevention of post surgical adhesions and, more particularly, concerns enhanced methods and compositions using a fibrin sealant to prevent such adhesions.
Formation of tissue adhesions between adjacent tissues is an adverse side effect of many surgical procedures. It is believed that following abdominal surgery the incidence of peritoneal adhesion formation may be as high as 90%. These post surgical adhesions often lead to pain, discomfort, immobility and, in the case of gynecological surgery, female infertility. Also, post surgical adhesions may even result in life-threatening bowel strangulation is some instances. Thus, there exists a large unmet need for a way to prevent post surgical adhesions, given the potential discomfort and medical risks they pose following routine surgery and the accompanying financial burden of remedying this adverse effect.
A number of pathways have been investigated to reduce or prevent post surgical adhesions. One proposed mechanism involves the reduction of the inflammatory reaction at the wounded site following surgery. In this regard, the use of corticosteroids, NSAIDS, histamine antagonists and calcium channel blockers has been suggested. Another prevention method recommends the inhibition of coagulation at the wounded site using, e.g., heparin or oral anticoagulants. Still further methods entail the promotion of fibrinolysis through appropriate administration of, for example, fibrinolysin, Streptokinase, Urokinase and t-PA. More recently, barrier materials have been suggested for the prevention of post surgical adhesions. The include, but are not limited to, amniotic membrane, rubber, silver foil, Teflon, dextran, hyaluronic acid, Surgigel(copyright) (regenerated cellulose), Interceed(copyright) (TC7 oxidized, regenerated cellulose), Polaxamer 407 (temperature dependent polymer), Gore-Tex(copyright) (expanded polytetrafluorethylene) and SepraFilm(copyright) (hyaluronic acid derivative film).
The above materials and methods fall into two basic categories; those which do not work effectively, and those which may provide some efficacy but are limited in either their use or applicability. Accordingly, new efforts have continued in this area.
The role of fibrin sealants in surgical procedures generally has been reviewed for many years. The role of fibrin sealants preventing or reducing of post surgical adhesions has been investigated over the past few years and is not totally understood at this time. Indeed, the literature in this area seems somewhat divided. Several researchers have reported an improvement in post surgical adhesion prevention using fibrin sealants. For example, the incidence of parovarian adhesions was significantly reduced in women subjected to laser vaporization of endometriomas and fibrin sealant (Donner, J. et al.; J Gynecol Surg 7:163, 1991), incisioned and colonic adhesions formation was reduced in abraded rabbit uterine horns (Chmielewski, G. et al.; The American Surgeon Vol 58 No. 9; 590, 1992), intrabdominal adhesion formation was reduced in rats (deVirgilio, et al.; Aarch Surg Vol 125; 1378, 1990), epidural scar formation in rats was reduced after laminectomy (Vaquero, J. et al.; Acta Neurochir (Wien) 120; 159-163, 1993) and flexor tendon adhesion formation in rabbits was reduced following a partial laceration of the flexor tendon (Fryknra, E. et al.; Journal of Hand Surgery Vol. 18A, No. 1; 68, 1993).
Others reporting on the use of fibrin sealants to prevent post surgical adhesions have not been so positive. For example, fibrin sealant was found to have no statistically significant effect in preventing perivascular adhesions following arteriotemics of the femoral and carotid arteries of dogs (Dickinson, C. et al., Vascular Surgery; 15, 1993); fibrin sealant did not prevent adhesion formation in colonic anastomoses in the rat (van der Ham, A., et al.; J Surgical Research, 55; 256-260, 1993) and fibrin sealant did not reduce post surgical adhesions following ovarian reconstruction in the rabbit (Bilgin, T., et al.; Gynecol Obstet Invest 39; 186-187, 1995).
WO 92/22312 to Wadstrom discloses combinations of fibrin sealants and biocompatible polymers reportedly useful for the prevention of post surgical adhesions. WO 92/22312 reports that fibrin sealants alone provide a wound healing effect which results in strong scar formation and does not prevent adhesions. The viscosity enhancing polymers are useful to allow application of the otherwise watery sealant components to vertical surfaces and also prevents adhesions. These polymers are high molecular polyglycans or polysaccharides.
WO 96/22115 discloses a self supporting sheet material of cross-linked fibrin having a particular range of pore sizes to prevent or reduce post surgical adhesions. The use of spray application to prepare these and similar sheets is reported in WO 98/02098. These sheets are described as generally non-adherent and non-hemostatic and are preferably used in conjunction with a known fibrin sealant which does possess adherence and hemostatic capabilities. These sheets are prepared using high concentrations of fibrinogen and high dose thrombin to obtain the desired structure regarding pore size and distribution (preferably  less than 20 xcexcm, more preferably  less than 5 xcexcm, most preferably  less than 1 xcexcm). Also, the sheet is pre-formed outside of the body and needs to be applied as a solid material, i.e., not applied as a spray or liquid.
Since fibrin sealants are used increasingly for hemostasis and fluid and air leakage in surgical procedures, it is important that a sealant is used which does not promote adhesion formation. Also, since fibrin is a part of the natural healing process it seems desirable to attempt to use fibrin in resolving the post surgical adhesions problem, as well. It would be preferable to be able to accomplish this without polymer additives, without high concentrations of fibrinogen, without subjecting the patient to high dose thrombin and, preferably, without the need for preformed sheets which must, in turn, be used with standard sealants. A more natural, single-step sealant/hemostat/adherent/adhesion barrier, preferably applicable by spraying and preferably free of added thrombin would be a significant advance in the art.